Congestive heart failure (CHF) causes the death of 250,000 Americans each year. The majority of cases result from myocardial infarction (MI) induced left ventricular (LV) remodeling. Remodeling is manifest by LV dilatation and global loss of contractile function; significant mitral regurgitation (ischemic mitral regurgitation- IMR) develops in at least 35% of these patients and may exacerbate the phenomenon. The goal of this project is use well characterized and clinically relevant ovine infarction models to elucidate the mechanism of post MI remodeling to an extent that has not been previously possible. We will focus on two common mechanical sequelae of MI: infarct expansion and IMR. In Specific Aim 1, we test the hypothesis that infarct expansion (stretching) drives LV remodeling by increasing stress in the borderzone (BZ) myocardium. Increased BZ stress produces a self-perpetuating phenomenon by decreasing contractile strain in the region and causing inherent changes in myocyte and extracellular matrix biology that allows for propagation of the abnormal stress fields to progressively more remote myocardial regions. We have developed innovative and powerful technical capabilities to quantitatively assess all components of this pathologic cascade. Optical flow mapping of tagged MRI images will be used to measure truly 3D myocardial strains. Myocardial stress distribution will be calculated using state-of-the-art finite element analysis based on the MRI strain data. Infarct material properties will be measured using biaxial mechanical testing. In Specific Aim 1 three therapeutic approaches to limit infarct expansion early after MI will be studied: heart wrapping with the Acorn CSD(R), infarct reperfusion and calcium hydroxyapatite microsphere gel injection. In Specific Aim 2 using the same tools we focus on treating the chronically remodeled heart and test the hypothesis that even small (<4.5%) fractional changes in LV wall volume (caused by calcium hydroxyapatite microsphere gel injection) can significantly improve cardiac mechanics when optimally located. In Specific Aim 3 we focus on the chronically remodeled heart with IMR and test the hypothesis that surgical repair techniques that are designed to increase mitral leaflet curvature (and theoretically reduce leaflet/chordal stress) will be superior to flat ring annuloplasty in improving regional and global LV function in severely remodeled hearts with established IMR. Saddle-shaped annuloplasty and leaflet augmentation will be used to manipulate leaflet curvature. A novel 3D echocardiography based approach to measuring leaflet geometry will be used. PUBLIC HEALTH RELEVANCE: This project seeks to determine the mechanism of post infarction left ventricular remodeling. The contribution of infarct expansion and ischemic mitral regurgitation will be studied. Powerful new imaging and analytic tools will be used to elucidate how time- dependent changes in infarct material properties and mitral-ventricular interactions influence regional myocardial stress distribution, regional contractile function and regional myocyte and extracellular matrix biology. The affect of novel early and late therapies on the remodeling process will also be assessed.